LRFN3 (leucine rich repeat and fibronectin type III domain containing 3) is a neuronal transmembrane glycoprotein belonging to the LRR-Ig-Fn superfamily of cell adhesion molecules. It mediates homophilic, calcium-independent cell-cell adhesion and promotes neurite outgrowth in hippocampal neurons. LRFN3 contains leucine-rich repeat, immunoglobulin-like, and fibronectin type III domains, with an extracellular N-terminus and intracellular C-terminus that can bind PDZ domains of postsynaptic scaffolding proteins like PSD95, suggesting a role in synaptic organization 1. The gene is predominantly expressed in the adult mouse and human brain, with expression initiated during immature neural cell development 1. Beyond its canonical neuronal functions, LRFN3 has emerged as a candidate gene in several disease contexts. It harbors a neoantigen mutation (R118Q) that induced heightened neoantigen-reactive T cell responses in colorectal cancer patients, with potential immunotherapeutic applications 2. LRFN3 shows frequent chr19 gains in embryonal rhabdomyosarcoma, suggesting a role in sarcoma pathogenesis 3. Additionally, LRFN3 carries multiple genetic variants associated with opioid use disorder, functioning within calcium signaling and opioid addiction pathways 4. Recent evidence links LRFN3 to inflammatory bowel disease susceptibility through ancestry-specific African alleles 5, and to rheumatoid arthritis via glycolysis-related gene networks 6. These findings indicate LRFN3's broader involvement in immune-mediated and metabolic disease pathogenesis beyond its primary neurobiological function.